Early restenosis is the major complication of percutaneous transluminal coronary angioplasty (PTCA), occurring in ≈30% of all initially successful procedures. The D/I polymorphism of the ACE gene, which has variably been reported to represent a risk factor for manifestations of ischemic heart disease, has recently been implicated in the pathophysiology of restenosis after PTCA by some investigators but not by others. All studies conducted thus far involved relatively small sample sizes. We investigated the possible association of ACE D/I genotype and post-PTCA restenosis in a large, prospective sample of patients followed by quantitative coronary angiography. The ACE D/I gene polymorphism was characterized in a cohort of 779 patients, of whom 342 (cases) had developed restenosis (as defined by >50% loss of lumen compared with immediate postprocedure results) at repeat quantitative coronary angiography at 6 months after PTCA. Allele frequencies for the ACE D and I alleles were 0.58 and 0.42 in cases and 0.58 and 0.42 in control subjects. All observed genotype frequencies were in Hardy-Weinberg equilibrium. There was no evidence for an association between genotype and restenosis or degree of lumen loss. The data from this largest study of its kind conducted so far provide no evidence for an association of the ACE D/I allelic polymorphism with incidence of restenosis after PTCA. On the basis of the power of this study, we conclude that in a general population, the ACE D/I polymorphism is not a useful marker to assess risk of post-PTCA restenosis.